Methamphetamine (MA) directly releases dopamine and norepinephrine from presynaptic neurons, but also alters the functioning of cholinergic neurotransmitter systems. Medications targeting acetylcholine have not received adequate attention as treatments for MA dependence. We recently completed a double-blind placebocontrolled human laboratory study demonstrating that treatment with a 3mg dose of the acetylcholinesterase (AChE) inhibitor rivastigmine significantly attenuated MA-induced craving. This finding is consistent with a preclinical report indicating that treatment with the AChE inhibitor donepezil reduced MA-seeking behavior in rats following exposure to a non-contingent dose of MA (Hiranita et al. 2006). To extend our clinical findings, we propose a 3-year human laboratory study to evaluate effects of higher doses of rivastigmine on MA-induced craving and on self-administration of MA. In order to ensure that participants have the target symptom, we propose to screen participants prior to randomization and will retain only participants exhibiting MA-induced craving in the laboratory. Effects of rivastigmine on the reinforcing effects of MA will be assessed using a questionnaire and using intravenous self-administration procedures. The project has the following objective: In non-treatment-seeking, MA-dependent volunteers, to characterize the effects of treatment with rivastigmine (0, 3, 6, or 12mg) on craving produced by experimental administration of MA (0, 15, and 30mg, IV). Hypothesis 1. Rivastigmine treatment will dose-dependently reduce MA-induced craving. Hypothesis 2. Rivastigmine treatment will reduce choices for MA in a selfadministration paradigm. The proposed work represents an important research effort with considerable public health significance in that it will establish a program for evaluating compounds targeted specifically at nicotinic ACh receptor activation for the treatment of MA dependence. The knowledge gained may ultimately support development and implementation of evidence-based treatments for MA dependence, a drug abuse problem with tremendous public health impact. [unreadable] [unreadable] [unreadable] [unreadable]